This research grant application is submitted in direct response to RFA 89-10, which requests research proponals Idetermining intra-cellular kinetics of endogenous metabolite pools in calls in culturs, and hov theas kinetics are affected by treatment vith analogous therapoutic agents or other potential AIDS therapies.1 In accord with the objectives of the RFA, the current proponal aing specifically: (1) to apply recently developed and sonsitive laboling tachniques to quantitate the intracallular kineties of pyrimidine and purine deoxynucleotide metabolites in human T lymphoblant and pro-sonocyto coll lines, and in peripheral blood monocytes and macrophages, (2) to compare the metabolian in lymphocytes and monocytes of dideoxynucloosides vith anti-HIV activity (AZT, ddC, ddA, 2-chloro-ddA, ddI, and others), and their effects on deoxynucleotide pool kinetics; and (3) to use novel cell lines with genetic alterations in nucleoside metabolism to demonstrate how changes in deoxynuclootide pool kinetics can affect the metabolism, toxicity, and potential anti-HIV activity of dideoxynucleosides. The results of these studies should provide a rational basis for the further pharmacologic evaluation of dideoxynuleosides for the treatment of HIV infection.